Rationale and design of the PreventIon of CArdiovascular events in iSchemic Stroke patients with high risk of cerebral hemOrrhage (PICASSO) study: A randomized controlled trial

Abstract

Rationale: Prior intracerebral haemorrhage and cerebral microbleeds may increase the risk of haemorrhagic stroke. However, the optimal long-term antiplatelet therapy and lipid management in these patients remain unclear.

Aim: PreventIon of CArdiovascular events in iSchemic Stroke patients with high risk of cerebral hemOrrhage was designed to compare cilostazol and aspirin and to assess the effect of adding probucol, a lipid-lowering and anti-oxidative agent, in patients at high risk of haemorrhagic stroke.

Sample size estimate: The projected sample size is 1600 patients with at least 12 months of follow-up.

Methods and design: PreventIon of CArdiovascular events in iSchemic Stroke patients with high risk of cerebral hemOrrhage is a randomized trial involving 67 institutes from 3 countries. Patients with non-cardioembolic ischemic stroke or transient ischemic attack within 180 days and with prior intracerebral haemorrhage or multiple cerebral microbleeds on gradient echo imaging are eligible. Enrolled patients are simultaneously randomized in a 2 × 2 factorial design: double-blind for cilostazol 200 mg/day vs. aspirin 100 mg/day, and an open-label, blind end-point evaluation for probucol 500 mg/day vs. non-probucol.

Study outcomes: The co-primary end-points are the safety end-point of haemorrhagic stroke and the efficacy end-point of a composite of stroke, myocardial infarction, or vascular death. Time-to-event will be analyzed separately for each intervention: superiority testing for the safety of cilostazol over aspirin as well as the efficacy of probucol over non-probucol, and non-inferiority testing for the efficacy of cilostazol to aspirin.

Discussion: PreventIon of CArdiovascular events in iSchemic Stroke patients with high risk of cerebral hemOrrhage is the largest secondary stroke prevention trial for informing antiplatelet therapy and lipid management in patients at high risk of haemorrhagic stroke.

Keywords: cerebral infarction; cilostazol; clinical trial; intracerebral haemorrhage; microbleeds; probucol.